PROJECT SUMMARY Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders with severe socioeconomic impacts and unknown pathogenesis. Circular RNAs (circRNAs) are a novel category of non- coding RNAs that are derived from the back-splicing and covalent joining of exons and introns of protein- coding genes, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are relatively enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neuropsychiatric disease. Here we carried out systematic profiling of circRNA expression in a large cohort of human postmortem brains from subjects with SCZ and BD and uncovered a subset of differentially expressed circRNAs produced from genes with known links to synaptic plasticity and neuronal excitability. We propose to study the function of the evolutionary conserved, neuronal-enriched circRNA, circHomer1, which is reduced in both the prefrontal cortex (PFC) of both BD and SCZ postmortem brains and in patient-derived neuronal cultures. We hypothesize that circHomer1 inhibits glutamatergic synaptic transmission and neuronal excitiability via inhibiting the expression and synaptic localization of plasticity-related Homer protein homolog 1 long isoform B (HOMER1B) mRNA, thereby disrupting PFC functions. We intend to knockdown circHomer1 expression in both induced pluripotent stem cell (iPSC)-derived neuronal cultures and mouse PFC and examine its role in neuronal fuction and psychiatric disease-related behavior. We will test our hypothesis via three specific aims: 1) Test the hypothesis that circHomer1 and HOMER1B mRNA levels are differentially altered in a cell-specific manner in human PFC and iPSC-derived neuronal cultures from patients with psychiatric disease. 2) Test the hypothesis that circHomer1 regulates synaptic efficacy and neuronal excitability through inhibition of HOMER1B localization. 3) Test the hypothesis that circHomer1 deficits in the PFC influence neuronal firing, cognitive flexibility, and sensorimotor gating.